Olav Sletvold

LMNA mutations in atypical Werner's syndrome

BACKGROUND Werners syndrome is a progeroid syndrome caused by mutations at the WRN helicase locus. Some features of this disorder are also present in laminopathies caused by mutant LMNA encoding nuclear lamin A/C. Because of this similarity, we sequenced LMNA in individuals with atypical Werners syndrome (wild-type WRN). METHODS Of 129 index patients referred to our international registry for molecular diagnosis of Werners syndrome, 26 (20%) had wildtype WRN coding regions and were categorised as having atypical Werners syndrome on the basis of molecular criteria. We sequenced all exons of LMNA in these individuals. Mutations were confirmed at the mRNA level by RT-PCR sequencing. In one patient in whom an LMNA mutation was detected and fibroblasts were available, we established nuclear morphology and subnuclear localisation. FINDINGS In four (15%) of 26 patients with atypical Werners syndrome, we noted heterozygosity for novel missense mutations in LMNA, specifically A57P, R133L (in two people), and L140R. The mutations altered relatively conserved residues within lamin A/C. Fibroblasts from the patient with the L140R mutation had a substantially enhanced proportion of nuclei with altered morphology and mislocalised lamins. Individuals with atypical Werners syndrome with mutations in LMNA had a more severe phenotype than did those with the disorder due to mutant WRN. INTERPRETATION Our findings indicate that Werners syndrome is molecularly heterogeneous, and a subset of the disorder can be judged a laminopathy.

Comprehensive geriatric care for patients with hip fractures: a prospective, randomised, controlled trial

BACKGROUND Most patients with hip fractures are characterised by older age (>70 years), frailty, and functional deterioration, and their long-term outcomes are poor with increased costs. We compared the effectiveness and cost-effectiveness of giving these patients comprehensive geriatric care in a dedicated geriatric ward versus the usual orthopaedic care. METHODS We did a prospective, single-centre, randomised, parallel-group, controlled trial. Between April 18, 2008, and Dec 30, 2010, we randomly assigned home-dwelling patients with hip-fractures aged 70 years or older who were able to walk 10 m before their fracture, to either comprehensive geriatric care or orthopaedic care in the emergency department, to achieve the required sample of 400 patients. Randomisation was achieved via a web-based, computer-generated, block method with unknown block sizes. The primary outcome, analysed by intention to treat, was mobility measured with the Short Physical Performance Battery (SPPB) 4 months after surgery for the fracture. The type of treatment was not concealed from the patients or staff delivering the care, and assessors were only partly masked to the treatment during follow-up. This trial is registered with ClinicalTrials.gov, number NCT00667914. FINDINGS We assessed 1077 patients for eligibility, and excluded 680, mainly for not meeting the inclusion criteria such as living in a nursing home or being aged less than 70 years. Of the remaining patients, we randomly assigned 198 to comprehensive geriatric care and 199 to orthopaedic care. At 4 months, 174 patients remained in the comprehensive geriatric care group and 170 in the orthopaedic care group; the main reason for dropout was death. Mean SPPB scores at 4 months were 5·12 (SE 0·20) for comprehensive geriatric care and 4·38 (SE 0·20) for orthopaedic care (between-group difference 0·74, 95% CI 0·18-1·30, p=0·010). INTERPRETATION Immediate admission of patients aged 70 years or more with a hip fracture to comprehensive geriatric care in a dedicated ward improved mobility at 4 months, compared with the usual orthopaedic care. The results suggest that the treatment of older patients with hip fractures should be organised as orthogeriatric care. FUNDING Norwegian Research Council, Central Norway Regional Health Authority, St Olav Hospital Trust and Fund for Research and Innovation, Liaison Committee between Central Norway Regional Health Authority and the Norwegian University of Science and Technology, the Department of Neuroscience at the Norwegian University of Science and Technology, Foundation for Scientific and Industrial Research at the Norwegian Institute of Technology (SINTEF), and the Municipality of Trondheim.

Evaluation of a Body-Worn Sensor System to Measure Physical Activity in Older People With Impaired Function

Background There is limited information on reliable and valid measures of physical activity in older people with impaired function. Objective This study was conducted to compare the accuracy of single-axis accelerometers in recognizing postures and transitions and step counting with the accuracy of video recordings in people with stroke (n=14), older inpatients (n=14), people with hip fracture (n=8), and a reference group of 10 adults who were healthy. Design This was a cross-sectional study, evaluating the concurrent validity of small body-worn accelerometers against video observations as the criterion measure. Methods Activity data were collected from 3 sensors (activPAL) attached to the thighs and the sternum and from registration of the same activities from video recordings. Participants performed a test protocol of in-bed, transfer, and walking activities. Results The sensor system was highly accurate in classifying lying, sitting, and standing positions (100%) and in recognizing transitions from lying to sitting positions and from sitting to standing positions (100%). Placement of a sensor on the nonaffected leg resulted in less underestimation of step counts than placement on the affected leg. Still, the sensor system underestimated step counts during walking, especially at slow walking speeds (≤0.47 m/s) (limits of agreement=−2.01 to 16.54, absolute percent error=40.31). Limitations The study was performed in a controlled setting and not during the natural performance of activities. Conclusions The activPAL sensor system provides valid measures of postures and transitions in older people with impaired walking ability. Step counting needs to be improved for the sensor system to be acceptable for this population, especially at slow walking speeds.

Reduced mortality in treating acutely sick, frail older patients in a geriatric evaluation and management unit. A prospective randomized trial.

OBJECTIVES: Documentation of treatment effects in acutely sick frail older patients in geriatric evaluation and management units (GEMUs) is scarce. The present study evaluated whether treatment in a GEMU would reduce mortality as compared to traditional treatment delivered in the Department of Internal Medicine.

APOE ε4 lowers age at onset and is a high risk factor for Alzheimer's disease; A case control study from central Norway

BackgroundThe objective of this study was to analyze factors influencing the risk and timing of Alzheimers disease (AD) in central Norway. The APOE ε4 allele is the only consistently identified risk factor for late onset Alzheimers disease (LOAD). We have described the allele frequencies of the apolipoprotein E gene (APOE) in a large population of patients with AD compared to the frequencies in a cognitively-normal control group, and estimated the effect of the APOE ε4 allele on the risk and the age at onset of AD in this population.Methods376 patients diagnosed with AD and 561 cognitively-normal control individuals with no known first degree relatives with dementia were genotyped for the APOE alleles. Allele frequencies and genotypes in patients and control individuals were compared. Odds Ratio for developing AD in different genotypes was calculated.ResultsOdds Ratio (OR) for developing AD was significantly increased in carriers of the APOE ε4 allele compared to individuals with the APOE ε3/ε3 genotype. Individuals carrying APOE ε4/ε4 had OR of 12.9 for developing AD, while carriers of APOE ε2/ε4 and APOE ε3/ε4 had OR of 3.2 and 4.2 respectively. The effect of the APOE ε4 allele was weaker with increasing age. Carrying the APOE ε2 allele showed no significant protective effect against AD and did not influence age at onset of the disease. Onset in LOAD patients was significantly reduced in a dose dependent manner from 78.4 years in patients without the APOE ε4 allele, to 75.3 in carriers of one APOE ε4 allele and 72.9 in carriers of two APOE ε4 alleles. Age at onset in early onset AD (EOAD) was not influenced by APOE ε4 alleles.ConclusionAPOE ε4 is a very strong risk factor for AD in the population of central Norway, and lowers age at onset of LOAD significantly.

Unwanted incidents during transition of geriatric patients from hospital to home: a prospective observational study

BackgroundGeriatric patients recently discharged from hospital experience increased chance of unplanned readmissions and admission to nursing homes. Several studies have shown that medication-related discrepancies are common. Few studies report unwanted incidents by other factors than medications. In 2002 an ambulatory team (AT) was established within the Department of Geriatrics, St. Olavs University Hospital HF, Trondheim, Norway. The AT monitored the transition of the patients from hospital to home and four weeks after discharge in order to reveal unwanted incidents.The aim of the present study was to describe unwanted incidents registered by the AT among patients discharged from a geriatric evaluation and management unit (GEMU) by character, frequency and stage in the transitional process. Only unwanted incidents with a severity making contact with the primary health care (PHC) necessary were registered.MethodsA prospective observational study with patients treated in the GEMU and followed by the AT was performed. Current practice included comprehensive geriatric assessment and management including discharge planning in the GEMU and collaboration with the primary health care on appointments on assistance to be provided after discharge from hospital. Unwanted incidents severe enough to induce contact with the primary health care were registered during the transitional phase and after discharge.Results118 patients (65% female), with mean age 83.2 ± 6.4 years participated. Median Barthel Index at discharge was 18 (interquartile range 16-19) and median Mini Mental Status Examination 24 (interquartile range 21-26). A total of 146 unwanted incidents were registered in 70 (59%) of the patients. Most frequent were unwanted incidents related to drug prescription regime (32%), exchange of information in and between the GEMU and the primary health care (25%) and service or help provided from the PHC (17%).ConclusionsDespite a seemingly well-organised system for transition of patients from the GEMU to their homes, one or more unwanted incidents occurred in most patients during discharge or four weeks post discharge. The study has revealed areas of importance for improving transitional care of geriatric patients.

Effects of home exercises and group training on functional abilities in home-dwelling older persons with mobility and balance problems. A randomized study

Background and aims: Exercise in older people may reduce falls and improve functional abilities. Less is known about the optimal amount of training. The aim of this study was to determine the effectiveness of home training, and whether group training in addition to home training enhances the effect. Methods: This randomized trial included 77 persons aged 75 years and older (mean 81, SD 4.5), living at home. Home training (HT) comprised twice-daily functional balance and strength exercises and 3 group meetings. Combined training (CT) included group training twice weekly and the same home exercises. The trial lasted 12 weeks. Physical therapists ran both programs. Exercises and falls were recorded daily. We assessed function at baseline, 3 and 9 months, and falls at one year. Results: Mean participation for group meetings was 2.5 out of 3 (HT group) and, for group training sessions, 21 out of 24 (CT group). The mean numbers of daily home sessions were 1.29 and 1.35 in the HT and CT groups. Overall improvement, but no group differences, were found at 3 months for walking speed, Figure of Eight, Timed Up & Go, Maximum Step Length, Timed Pick-up and Sit-to-stand (p<0.02). Posturography (p=0.85) and isometric quadriceps strength (p=0.26) showed no improvement. Function at 9 months was equivalent to baseline level. There were no group differences in fall rate (p=0.78) or time to first fall (p=0.84). Conclusions: Daily home training supervised by physical therapists improved functional abilities. Supplementary individualized group training gave no additional effect. The effect on function was not present 6 months after the end of the intervention.

Home training with and without additional group training in physically frail old people living at home: effect on health-related quality of life and ambulation

Objective: To test the effect of two exercise regimes on health-related quality of life (HRQoL) and ambulatory capacity. Design: Randomized controlled trial. Subjects: Seventy-seven community-dwelling physically frail people over 75 years of age (mean=81, SD=4.5). Interventions: Home training (HT, N =38) comprised twice daily functional balance and strength exercises and three group meetings. Combined training (CT, N =39) included group training twice weekly and the same home exercises. Interventions lasted 12 weeks. Physiotherapists ran both programmes. Home exercises were recorded daily. Main measures: HRQoL was assessed by SF-36, and ambulatory capacity by walking speed and frequency and duration of outdoor walks. Results: Following intervention, CT improved the SF-36 mental health index significantly more than HT (p =0.01). The SF-36 physical health index (p =0.002) and walking speed (p =0.02) demonstrated improvements, but no group differences. Six months after cessation of intervention there was still overall improvements on the mental health index (p =0.032), borderline overall improvements on the physical health index (p =0.057), higher weekly number of outdoor walks for the CT group than for the HT group (p =0.027) and an improved habitual walking speed in the CT group only (p =0.022). Conclusions: HT improved HRQoL and walking speed, but additional group training gave larger benefits on mental health. Group training away from home may be beneficial for mental health and ambulatory capacity.

Validation of the Falls Efficacy Scale-International in fall-prone older persons

SIR—Fear of falling in community-dwelling older persons [1, 2] may lead to activity restriction [3]. It can predict future falls [4] and is an important fall-related psychological outcome [5–9]. The widely used 10-item Falls Efficacy Scale (FES) [5] does not evaluate the social dimension of fear of falling and refers almost exclusively to very basic activities of daily living, making it insensitive when used in active older persons. To remedy this, a new 16-item Falls Efficacy Scale-International (FES-I) [10] has been developed by the Prevention of Falls Network Europe (ProFaNE, www.profane.eu.org), showing excellent psychometric properties in a cross-cultural context [11]. Furthermore, a seven-item FES-I has been developed and recommended for use as part of a test battery and for screening purposes [12]. The evaluation of the FES-I has so far been performed in community-dwelling non-clinical samples. To examine the relevance of the two FES-I versions for health care settings, further evaluation of the instrument should include fall-prone older persons. The aim of this study was to test the psychometric properties of the Norwegian version of the 16-item FES-I in samples of fall-prone older home-dwelling persons recruited from the health care system and to assess if the seven-item FES-I has the same properties as the 16-item FES-I in these samples.

Physical Behavior and Function Early After Hip Fracture Surgery in Patients Receiving Comprehensive Geriatric Care or Orthopedic Care—A Randomized Controlled Trial

BACKGROUND This study is a part of the randomized controlled trial, the Trondheim Hip Fracture Trial, and it compared physical behavior and function during the first postoperative days for hip fracture patients managed with comprehensive geriatric care (CGC) with those managed with orthopedic care (OC). METHODS Treatment comprised CGC with particular focus on mobilization, or OC. A total of 397 hip fracture patients, age 70 years or older, home dwelling, and able to walk 10 m before the fracture, were included. Primary outcome was measurement of upright time (standing and walking) recorded for 24 hours the fourth day postsurgery by a body-worn accelerometer-based activity monitor. Secondary outcomes were number of upright events on Day 4, need for assistance in ambulation measured by the Cumulated Ambulation score on Days 1-3, and lower limb function measured by the Short Physical Performance Battery on Day 5 postsurgery. RESULTS A total of 317 (CGC n = 175, OC n = 142) participants wore the activity monitor for a 24-hour period. CGC participants had significantly more upright time (mean 57.6 vs 45.1 min, p = .016), higher number of upright events (p = .005) and better Short Physical Performance Battery scores (p = .002), than the OC participants. Cumulated Ambulation score did not differ between groups (p = .234). CONCLUSIONS When treated with CGC, compared with OC, older persons suffering a hip fracture spent more time in upright, had more upright events, and had better lower limb function early after surgery despite no difference in their need for assistance during ambulation.